The 121st meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, February 25, 2014, at 3 p.m. in Building 31, Conference Room 6, National Institutes of Health (NIH), Bethesda, MD. Richard J. Hodes, M.D., director, National Institute on Aging (NIA), presided.

In accordance with the provisions of Public Law 92–463, the meeting was closed to the public on Tuesday, February 25, from 3 to 5 p.m. for the review, discussion, and evaluation of grant applications in accordance with the provisions set forth in Sections 552(b)(c)(4) and 552(b)(c)(6), Title 5, U.S. Code and Section 10(d) of the Public Law 92–463.1 The meeting was open to the public on Wednesday, February 26, from 8:00 a.m. to 1:00 p.m.

This portion of the meeting was closed to the public, in accordance with the determination that it concerned matters exempt from mandatory disclosure under Sections 552(b)(c)(4) and 552(b)(c)(6), Title 5, U.S. Code and Section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix).3

A total of 1034 applications requesting $1,612,425,777 for all years underwent initial review. The Council recommended 568 awards for a total of $1,021,461,856 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.

Dr. Hodes welcomed members to the open session of the 121st NACA meeting and called the meeting to order at 8:00 a.m. on Wednesday, February 26, 2014.

Director’s Status Report

Dr. Hodes began his report by reporting that a budget had been passed by Congress. The appropriations legislation restores approximately half of the funds lost to sequestration in FY2013, increasing the budget by about 2% for most NIH Institutes and Centers (ICs). An additional $100 million has been appropriated to NIA for aging research, including research on Alzheimer’s disease (AD). Dr. Hodes noted that, although the NIH budget is not back to pre-sequestration levels, the appropriations legislation is a positive signal.

The 2013 success rate for all research project grant applications submitted to NIA was about 14%, which Dr. Hodes acknowledged was historically low. Dr. Hodes also noted that, unlike the rest of NIH, which saw a slight decrease in the number of applications received between 2012 and 2013, NIA saw a 30% increase, which includes responses to requests for applications (RFAs). The tentative Research Project Grant (RPG) paylines for 2014 are not much different from 2013: 11% for projects requesting less than $500,000 and 8% for applications requesting $500,000 or more, among established principal investigators (PIs). Among projects requesting less than $500,000, paylines are 16% for R01 applications from early-stage investigators and 14% for R01s from other new investigators. The paylines are 3 percentage points lower, respectively, for projects requesting greater than $500,000. Dr. Hodes pointed out that despite the continued funding difficulties; the increased number of applications indicates an enthusiasm for aging research. He also reminded Council that NIA had imposed cuts to noncompeting awards in 2013 to offset the effects of sequestration, and he announced NIA’s intent to revert to pre-sequestration commitments this year.

NIA had issued RFAs for National Alzheimer’s Project Act (NAPA)- and AD Summit-related research initiatives while uncertain of funding. In 2013, Dr. Francis Collins, NIH Director, provided $40 million from the Office of the Director budget to aid with these initiatives. A portion of the 2014 budget for AD research will be used to fund three RFAs issued in 2013 and a recent RFA for planning grant for translational centers for predictive drug development. The rest will be used to support the best investigator-initiated applications received. NIA is also in the process of identifying candidate concepts for funding opportunity announcements (FOAs) for 2015; these concepts will be presented at the May 2014 Council meeting.

Dr. Hodes also reported on his participation in two Congressional Hearings. In January 2014, Dr. Hodes, as a member of the NAPA council, spoke to the House Foreign Affairs Subcommittee on Africa, Global Health, Global Human Rights, and International Organizations in a follow-up to the G-8 Summit held in London in December 2013. Dr. Hodes announced that he would be leaving the Council meeting early to attend a Senate Appropriations Subcommittee on Labor, HHS, and Education hearing on AD, where he would join NIH Director Francis Collins, M.D., and National Institute of Neurological Diseases and Stroke (NINDS) Director Story Landis, Ph.D.

Dr. Hodes reported on several NIA research highlights. A database on genetic epidemiological research on aging, which was supported by funds from the American Recovery and Reinvestment Act (ARRA), is now available through the database of Genotypes and Phenotypes (dbGaP). A recent publication from Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) reports a 10-year benefit associated with training in reasoning and speed of processing. Another recent paper from an NIA-supported investigator demonstrates in mice that parabiosis reverses the myocardial hypertrophy characteristic of age, providing clues into the mechanism underlying aging-related changes. The first set of sequences generated through the AD Sequencing Project, which was funded through NAPA, has been posted. This represents whole genome sequencing for members of families with multiple individuals affected by AD. This component of the project is expected to be completed in March 2014. Whole exome sequence data on additional individuals who either do or do not have AD is expected to be available by the summer. Dr. Hodes also reminded Council that applications for the 2014 Butler-Williams Scholars Program for investigators who are new to aging research or interested in health disparities research are due March 28. The program will be held in August.

Dr. Hodes concluded by reporting on NIH-wide initiatives, including the Accelerating Medicines Partnership (AMP) and the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative. NIA already has been working with many investigators who are involved in AMP; thus this initiative will amplify existing NIA-supported projects by adding biomarkers and imaging and by integrating bioinformatics across all studies. With respect to the BRAIN initiative, NIH has proposed a governance model to integrate all BRAIN ICs. This model proposes a Council that includes representatives from individual IC Advisory Councils.

Dr. Richard Mayeux pointed out the opportunities for cross-talk among many of the projects and initiatives Dr. Hodes described. Dr. Hodes noted that Dr. Mayeux’s proposal of a workshop to facilitate discussion among the various groups was a good one and that NIA is looking for the right timing.

Future Meeting Dates

The next four meeting dates of the NIA NACA all fall on Tuesday and Wednesday and will be held at the Natcher Building; the September 2015 meeting will be in Building 31.

May 20–21, 2014
September 16–17, 2014
January 27–28, 2015
May 12–13, 2015
September 16-17, 2015 (Wednesday and Thursday)

Consideration of Minutes of the Last Meeting

The minutes of the September 2013 meeting were considered. A motion was made, seconded, and passed unanimously to approve the minutes.

PRESENTATION: PCORI FALLS INITIATIVE

Dr. Steven Clauser, a Program Director for Improving Health case systems at the Patient Centered Outcomes Research Institute (PCORI) spoke to the Council about PCORI’s mission. It is a private, nonprofit organization created by the Patient Protection and Affordable Care Act (ACA). By legislative mandate, PCORI’s overall purpose is to assist patients, clinicians, purchasers, and policy-makers in making informed health care decisions, by using research to advance the quality and relevance of evidence and by disseminating research findings. PCORI will be held accountable for changing medical practice, specifically the extent to which research findings are used by health care decision-makers and the contributions of its research to reducing practice variation and health disparities. To that end, PCORI’s board of governors has set three strategic goals: to increase the quantity, quality, and timeliness of useful evidence to support health decisions; speed the implementation and use of patient-centered outcomes research; and influence clinical and health care research funded by others to be more patient-centered.

PCORI emphasizes comparative effectiveness research (CER) conducted in real-world settings to address practical questions of value to patients and clinicians. As mandated by ACA, this research also must be of high scientific quality. PCORI has therefore established 47 research standards grouped into 11 categories and encompassing the spectrum of research activities. PCORI also emphasizes engagement with patients and other health care stakeholders, developing a skilled community of patients, caregivers, health care administrators, and clinicians to assist in generating and prioritizing research topics and questions. This community also will participate in ensuring that the review and conduct of PCORI-sponsored research meets its standards of high quality, disseminating and implementing research findings where they will have the largest impact, and reviewing the portfolio to ensure its relevance and salience to health care stakeholders.

Since its establishment, PCORI has funded 279 research projects at a total of $464 million, in 37 states including the District of Columbia. It has organized its programs around five research priorities. Its funding strategies include targeted PCORI Funding Announcements (PFAs), initiatives supporting pragmatic clinical studies, broad PFAs, and awards that promote the infrastructure needed to foster engagement.

Dr. Clauser, pointed out that ACA specifically mentioned NIH as a collaborative partner for PCORI and that the PCORI Board and Strategic Plan work to develop that partnership. Contracts and memoranda of understanding between PCORI and NIH will be used to manage large, targeted announcements, where PCORI will provide funding and rely on NIH for infrastructure and specific expertise. The PCORI Falls Initiative, which is focused on the prevention of falls and injury among older adults, is one example of such collaboration. PCORI and NIA staff and leadership worked together to develop the RFA, NIA selected patient and stakeholder peer reviewers, and representatives from both agencies serve on the steering committee to oversee and manage the trial. Dr. Clauser noted that this is a trailblazing activity between PCORI and NIA, and he acknowledged Dr. Collins, Dr. Hodes, NIA staff and NACA for their work in making the initiative a reality.

In response to questions from Ms. Jennie Hansen, Dr. Clauser noted that PCORI has recognized the connections between improving health care systems and reducing health disparities and that his program intends to keep the PCORI program on health disparities informed during the Falls Initiative. He added that the Initiative will address subpopulations, particularly those with special needs in falls prevention.

Dr. Clauser also reminded Council that the legislative authorization for PCORI is in place through 2019 and that efforts are under way to determine how best to promote continuation of the Institute. For example, PCORI aims to front-load some of its research, so that interim findings will be available by the time Congress considers reauthorization.

Dr. Cummings noted that PCORI has developed a valuable resource of patients trained to understand research and those investigators could use their advice as they design studies. Dr. Clauser responded that PCORI is developing a resource to connect investigators with potential patient advisers and that investigators can contact the Institute to identify potential connections. He also pointed out that as a result of PCORI’s engagement awards, many communities are building infrastructure to promote such connections.

Dr. Eliseo Perez-Stable reported on three presentations heard by the Task Force during the previous afternoon. The first, by Dr. Meredith Temple-O’Connor, NIH Inclusion Policy Officer, provided an overview of policies on the inclusion of women and minorities in clinical research, which was mandated by law in 1993. NIH has reorganized its governance structure, and the process for reporting has been under re-evaluation since 2011. Guiding principles in this re-evaluation include a focus on the science, simplified and streamlined processes, consistency across NIH, increased value of reporting for investigators and staff, and enhanced communication between staff and investigators. Dr. Perez-Stable reported that the Task Force raised questions about accountability and potential rewards to investigators for ensuring diverse study samples.

The second presentation, by Dr. Larissa Avilés-Santa, of the National Heart, Lung, and Blood Institute, discussed the Hispanic Community Health Study/Study of Latinos. This observational study aims to identify the prevalence of cardiovascular and pulmonary diseases and other conditions, the prevalence of risk and protective factors, and the incidence and all-cause mortality of fatal and non-fatal cardiovascular and pulmonary events in the United States among Hispanics or Latinos of diverse nationalities. Sites in San Diego, Chicago, Miami, and the Bronx have been funded to conduct the study, and more than 16,000 individuals have been recruited. Of this study sample, 10,000 were older than 45 and 1,600 older than 65 years at baseline. Recruitment and baseline evaluation are complete, and data collection for the second visit has begun. The study is funded through 2019. Dr. Perez-Stable noted that although the study did not include cognitive screening, there are still opportunities to add cognitive measures. He also reported that analysis for a genome-wide association substudy is under way.

The third presentation, by Dr. Alex Smith, an emerging scholar from the University of California, San Francisco, described a study focused on disabilities in older adults from diverse communities, particularly perceptions about quality of life, successful aging, and communications about prognosis. This study took advantage of San Francisco’s On Lok program, which includes a diverse population of disabled older adults who would otherwise be in a skilled nursing facility, and it was conducted in English, Spanish, and Cantonese. When asked about their quality of life, the majority of study participants perceived their quality of life as “good,” despite their disability. Likewise, the majority of participants thought they had aged successfully. Two-thirds of participants preferred the idea of physicians talking to patients about their 1- and 5-year prognoses. There were no obvious racial or ethnic differences.

Dr. Perez-Stable closed his presentation by reminding Council members to encourage applications to the Butler-Williams Scholars program.

Dr. Reisa Sperling reiterated questions about rewards to incentivize investigators to recruit more diverse study populations, particularly for intensive clinical studies. She also suggested PCORI as a potential partner to develop resources to address this issue. Dr. Perez-Stable noted that recruitment of diverse populations will continue to be a topic of discussion. He also emphasized concerns that review committees pay more attention to the inclusion of women and minorities in study samples, rather than investigators simply checking a box on their applications.

2013 NIA Inclusion Report

Dr. Robin Barr referred the Council to the 2013 NIA Inclusion Report, which compiles minority and gender tracking data across all NIA protocols. Dr. Barr noted that foreign and domestic studies are not separated for this report. Neither are demography and epidemiology, which are more likely to include larger studies, separated from clinical studies. As a result, it is not unusual to find highly distorted outcomes, for example showing that 36% of the total sample is Asian. Dr. Barr explained this artifact by noting that among the 15 most populous studies supported by NIA, one study in China has enrolled 80,000 individuals and another in Indonesia has enrolled 30,000 individuals. Those two studies alone count for more than 50% of the Asian individuals in the NIA sample. A motion to approve the report was forwarded and seconded. The motion was approved unanimously.

Dr. Ana Cuervo reported on selected topics from the January 2014 meeting of the Council of Councils (CoC). One was the CoC Working Group on the Use of Chimpanzees in NIH-supported Research, which was established to determine how best to implement the recommendations and principles set forth by an Institute of Medicine (IOM) review. The Working Group recommended an additional review process, separate from scientific review, in which an independent evaluation panel assesses whether applications for the inclusion of chimpanzees meet the IOM criteria. The panel makes recommendations for approval to the CoC. It does not make recommendations for funding.

CoC also discussed the Science Education Partnership Award (SEPA) program, which offers creative mechanisms to increase public awareness of NIH and provides grants for K-12 teachers, schools, museums, and science centers. Although this has been a successful program that has actively engaged the community, its continuation has been questioned because it has been perceived to be beyond the purview of NIH. An initial plan had proposed consolidating SEPA with activities managed by the Smithsonian Institute. However, SEPA has recently received funding of $3 million per year. SEPA will now continue to fund non-competing applications and issue new awards based on recommendations CoC made in 2013. An FOA will be reissued for 2015.

CoC also heard about the NIH Leadership Forum, which focuses on core facilities and concerns related to redundancies and under-utilization among cores, variable organizations, and unclear business models. NIH leadership will work with institutions and core facility directors to evaluate whether cores can be consolidated to free up more funds for research. In particular, possible incentives for sharing and consolidation will be considered.

Dr. Cuervo also reported on a presentation given to CoC by the NIH Director. Although Dr. Collins noted that NIH had “turned a corner” with respect to the budget, he identified other challenges. For example, NIH continues to excel in making discoveries, but it faces challenges in identifying new and emerging fields of science. This issue might be compounded by current restraints in the budget, which might make study sections less willing to take risks. In other cases, ICs are increasing funding mechanisms, such as the Pioneer Awards, to support emerging fields, but this increase comes at the expense of R01 awards. There will be a review of study sections, and the applicant biosketch will be enhanced to collect information emphasizing actual contributions.

Other topics discussed by the CoC included issues with reproducibility and the Science of Behavior Change initiative. CoC also cleared concepts for further development into Common Fund program announcements.

REPORT: WORKING GROUP ON PROGRAM

The Working Group on Program considered several reports, concept clearances, and contract renewals, as well as renewal of the Statement of Understanding.

Clinical Trials Advisory Panel (CTAP) Report

CTAP met twice in 2013 and reviewed four proposals for clinical trials. Two of these were tabled, and two were encouraged to move forward. One of these, which will look at combined modalities to improve treatment following hip fracture, has been sent back for further refinement. The Working Group concluded that the CTAP process is a useful one in refining and targeting proposed clinical trials, and it accepted the CTAP report.

A motion for the Council to approve the CTAP report was forwarded and seconded. The motion was approved unanimously.

RFA Concept Clearances

DNA Translational Concept

This concept requests support for a translational medicine program focused on systems, in line with the recognition that AD is a complex disorder in systems physiology and networks affecting several brain regions as recommended by the Working Group on Program at is meeting the prior day. The proposed initiative will support planning grants to establish a platform focused on systems physiology, systems pharmacology, integrative models, clinical trials, and biomarker development. The Working Group motioned for the Council to approve this concept, which will bring together stakeholders to address commonalities for AD. The motion was seconded and approved unanimously by the Council.

Enhancing Cross-National Research in the Health and Retirement Survey (HRS)

The Division of Behavioral and Social Research (DBSR) developed this initiative in response to the recent review, which suggested harmonization among studies. This concept will support the development of standard measures across studies. The Working Group felt that this is a well-developed concept and made a motion for approval. The motion was seconded and approved unanimously by the Council.

Epigenetic Analyses of Aging as a Risk Factor for Chronic Disease and Degenerative Conditions

The proposed concept is a planning program to examine the role of posttranslational modifications related to aging and disease. It will take advantage of existing tissue banks and new quantitative technologies to measure DNA alterations. The Working Group noted the potential impact for outcomes, biomarkers, and therapies, and it recommended approval of the concept. The motion was seconded and passed unanimously by the Council.

M.D./Ph.D. T32 Initiative in Social Sciences

Dr. Laura Carstensen reported that this long-standing initiative in the National Institute of General Medical Sciences currently supports trainees across 43 M.D. /Ph.D. programs, for a total of more than 900 nationwide. Although trainees in the social sciences have received a large amount of benefit and gone on to become highly influential in their fields, there are few new trainees in the social sciences. The proposed concept will support training in social sciences such as economics, demography, sociology, and social epidemiology. The Working Group encouraged NIA to include psychology as well. The Working Group expressed enthusiasm for the concept and made a motion for the Council to approve it. This motion was seconded and passed unanimously by the Council.

Modulation of Age-Related Changes in Neuromuscular Junctions

This initiative, co-sponsored by the Division of Aging Biology (DAB) and the Division of Neuroscience (DN), is a set-aside and special review to foster communication and collaboration between the fields of neuroscience and muscle biology in the study of age-related changes in neuromuscular junctions. The Working Group expressed general enthusiasm for the initiative but noted that it focused primarily on mammalian systems. The inclusion of other model organisms, such as Caenorhabditis elegans, was recommended. The Working Group made a motion for the Council to approve the concept. The motion was seconded and passed unanimously by the Council.

Clinical Trials on the Effects of Interventions Aiming to Reduce Chronic Inflammation in Older Adults

The concept for these trials arose from several meetings, including a Division of Geriatrics and Clinical Gerontology workshop. The trial concept was sent to CTAP for review in 2013 and scored very well after revision. The initiative will be implemented in two phases. The first will involve an open competition to support trial design and the development of protocols and manuals. Following review of this pilot phase, a limited competition will be held for the second phase, which will involve implementation of a clinical trial among adults older than 70 years with a risk for disability and biomarkers for inflammation. The Working Group made a motion for this concept to be approved by the Council. The motion was seconded and passed unanimously by the Council.

Renewal of Grants for Early Medical and Surgical Specialist Transition to Aging Research (GEMSSTAR)

The GEMSSTAR program originated in 2008 with the intent to protect time for junior specialists and clinical scientists to ensure a strong core of physicians interested in aging research. Launched in 2011, the program has been very successful and generated an impressive amount of data. Although the Working Group expressed some concern about a recent drop in the number of K08 and other training awards, it recommended renewal of GEMSSTAR for 5 years. The motion was seconded and passed by the Council. Ms. Hansen reported a conflict of interest and abstained from voting.

Dr. Perez-Stable reported that, on the basis of an active discussion, the Working Group recommended that this concept be deferred for further development.

Contract Renewals

Dr. Morimoto reported on three proposed contract renewals. One is a long-standing colony that serves as a unique resource for investigators to evaluate animal models of advanced age. The second provides pathology monitoring for this colony. The third supports more than 200,000 cell lines and related biologic materials that are used heavily by investigators in academia and biopharmacy. The Working Group noted the three as critical long-standing resources and motioned that these contracts be renewed. The motion was seconded and passed unanimously by the Council.

Dr. Carstensen reported on a DN proposal that follows a memorandum of understanding established between NIA and the Federal Communications Commission (FCC) in 2013. This partnership will work on a rigorous agenda on current and experimental use in telecommunications relay service technologies to serve American older adults with hearing disabilities or deafness. The FCC will provide funding and collaborate with NIA to develop a research plan to evaluate effectiveness, efficiency, and user satisfaction, among other components. The Working Group recommended that this contract be approved. The motion was seconded and passed unanimously by the Council.

Division of Behavioral and Social Research Final Program Report

Dr. Jonathan Skinner presented the final report from the DBSR Review Committee, which he co-chaired with Dr. Carstensen. He highlighted results from research supported by the Division, and presented overarching research recommendations from the Committee that centers on the following for middle-aged and older adults:

The pathways by which social, psychological, economic, and behavioral factors affect health.

How modifying organizational and individual behaviors is associated with positive and negative aging outcomes.

Factors that affect population aging, as well as the consequences of population aging, including increased emphasis on the social demography and social epidemiology of aging, and the dynamics of disability trends over time.

Mechanisms to ameliorate the impact of disadvantaged position in society, including factors associated with race/ethnicity and social class.

Dr. Skinner reminded the Council that the Committee divided into nine subcommittees, each of which generated a subcommittee report from which main findings were integrated into the overall Committee report. Across all subcommittee reports were calls for a continued strong emphasis on the integration of biology, social, and behavioral science; harmonization among national and international studies; and integration of randomized, clinical trials and other interventional trials with existing observational studies. The Committee also encouraged DBSR to take advantage of Big Data. With respect to training, the Committee encouraged continued support for T32 and F32 grants, but it urged greater flexibility among K awards to include support for cross-disciplinary research training. The Committee also commented on the grants review process, calling for special interdisciplinary review groups and careful review of potential infrastructure projects. Finally, the Committee acknowledged DBSR staff as a stellar team of scientist-administrators who bring new and innovative ideas, but it also cited continued recruitment as a top priority and encouraged DBSR to be careful and selective in its collaborations across staff levels.

Dr. Skinner concluded by citing DBSR’s outstanding progress since its 2008 review and emphasizing the importance of behavioral and social research for an aging population. He also acknowledged the leadership of Dr. Richard Suzman, DBSR Director. Dr. Carstensen also thanked BSR staff and Rose Li and Associates, Inc., for their assistance in developing the Committee’s report.

A motion to accept the report was forwarded and seconded. The motion was approved unanimously.

Report on the Trans-NIH Geroscience Interest Group (GSIG) Summit

Dr. Morimoto reported on a summary of outcomes from this Summit, which included 20 ICs and was led by staff from all NIA Divisions. A report, which extracted key points, is now available. The Working Group on Program encouraged GSIG to keep working to forge collaborations across all ICs.

Statement of Understanding

Dr. Barr reminded the Council that the Statement of Understanding is an agreement between NACA and NIA staff on routine business, such as small supplements or reinstatements, that can be done without Council action. This statement was modified in 2013 to increase the threshold for expedited applications to $500,000 and to allow for early concurrence. The statement was not modified this year.

A motion to approve the Statement of Understanding was forwarded and seconded. The motion passed unanimously.

PRESENTATION: THE PROMISE OF INTEGRATING CENTER CORES

Dr. James Anderson, Director of the Division of Program Coordination, Planning, and Strategic Initiatives (DPCPSI), provided perspectives on NIH-supported research core facilities, defined as centralized and shared resources that provide access to instruments, technologies, services, and consultations. These facilities have dedicated personnel, equipment, and space and attempt to recover costs via user fees. Although core facilities are supported by several mechanisms, Dr. Anderson focused his remarks on P30 and P50/60 grants, which form the largest fraction of NIH support.

Dr. Anderson reminded the Council that the NIH Leadership Forum had noted significant variability across institutions in management, scope, orientation, and total funding for core facilities. The Trans-NIH Core Working Group, which includes individuals from several ICs, was tasked with further assessing the core facility system. This Working Group looked at 2013 data from IMPAC II to generate a snapshot of how much ICs spend on funding mechanisms for core facilities and how these facilities are used. The snapshot reveals an approximate total cost of $2 billion across P30, P50/60, and U54 mechanisms and that half of these costs were associated with core facilities. It also reveals that half the funding across these mechanisms went to 30 institutions. Dr. Anderson cautioned that this is a conservative estimate. For example, because the database assigns costs to the lead IC, it does not provide a full representation of what each IC spent on core facilities. He also noted limitations in using IMPAC II, which is designed as a grants management tool, to characterize the cores. Despite these caveats, the Trans-NIH Core Working Group acknowledged the fundamental importance of cores, but it also suggested that NIH identify opportunities to improve efficiency.

This effort aligns with a formal review led in 2009 by the National Center for Research Resources and the Office for Extramural Research, which consisted of a request for information and two large workshops. This review raised several concerns:

A strong desire for a central directory of information about core facilities.

A large amount of variability in business practices among cores.

Debate on the benefits of centralized versus decentralized core management.

Concern about support for staff, particularly when funding for the core facility is intermittent.

The funding of similar cores by multiple ICs leading to duplication and underutilization.

Difficulty in understanding Circulars A21/A122 from the Office of Management and Budget pertaining to cost principles.

Comments from research deans also raised concerns about institutional liabilities associated with cores, the requirement of the institution to fund some activities not covered by other funding mechanisms, and grants review processes that discourage sharing.

Dr. Anderson reported on an ARRA-funded initiative that experimented with the consolidation of core facilities. Twelve ICs participated in this initiative, which required that consolidated cores be widely available, that they comply with the requirements of initial grants, and that institutions share their best practices for consolidation. So far, the initiative appears to be successful.

Dr. Mayeux noted inconsistencies in how core facilities are reviewed. For example, one AD Research Center (ADRC) core was criticized for supporting Parkinson’s disease and amyotrophic lateral sclerosis research but not specifying how much support went to each, whereas recent ADRC programs encouraged cores that facilitate research across the institution. Dr. Mayeux also called for a new model of support and management of core facilities, to keep costs low, and he warned about the underappreciation of Big Data. Dr. Anderson acknowledged Big Data as a major limitation in biomedical research and summarized recent NIH efforts to address this concern. For example, NIH has hired an Associate Director for Data Science, and the Common Fund is supporting the Big Data to Knowledge initiative.

Dr. Kevin High suggested that a directory of core services would provide a large return on investment, because investigators at smaller research institutions have difficulty in accessing cores. He suggested that such directories could improve efficiency by regionalizing facilities and by offering easy access and clear contact information. Dr. Morimoto echoed this sentiment, citing a strategy in which research directors from all Chicago-area research institutions formed a consortium and developed a mechanism for investigators to access core facilities at member institutions. Dr. Morimoto noted that this strategy allowed the use of core facilities to be market driven, because investigators could use the best facilities for the same cost. When asked how NIH could support best practices such as that strategy, Dr. Morimoto noted that word about such strategies starts to circulate as investigators attend meetings and workshops.

Council members suggested incentivizing institutions to identify inefficiencies, for example by providing the same cost structure but allowing institutions to recover additional research funds from such an effort. Other members suggested evaluating how effectively Centers’ programs, such as the ADRC program, use common cores across institutions, and yet others suggested partnering with industry to provide incentive for consolidation. Dr. Hodes also noted that almost all NINDS-supported Parkinson’s disease Udall Centers are located at institutions that have ADRCs. He suggested these institutions as places to experiment with consolidation.

The discussion concluded with Council members acknowledging many opportunities for consolidation or sharing, but cautioning that some components might be served better locally. For example, Dr. Bradley Hyman pointed out that the core facilities within the ADRC programs provide local expertise beyond simple services. Council members also suggested that NIH re-examine the grant processes that have led to an explosion of cores. For example, Dr. Morimoto pointed out that many of these processes were initiated when particular technologies were still nascent, but opportunities for sharing or consolidation have increased as the science has changed.

Division of Neuroscience (DN): Deconstructing the Genomic and Neuroimmunologic Architecture of Aging-Related Cognitive Decline and Dementia

Dr. Philip de Jager, of Brigham and Women’s Hospital and Harvard University, described comprehensive and collaborative work exploring the architecture of age-related cognitive decline and AD. This work takes advantage of two cohort studies—the Religious Orders Study and the Memory and Aging Project—which together include more than 2,700 participants and 1,100 autopsies of deceased participants. Dr. de Jager and his collaborators have combined genomic analyses with mass spectroscopy, quantitative neuropathology, and clinical data to identify genetic variants associated with different rates of cognitive decline and to examine how clinically observed pathology mediates the effects of these variants. For example, they have demonstrated that neuritic plaques and neurofibrillary tangles diminish the effects of a CR1 variant, which has been identified in genome-wide association studies as a susceptibility locus for AD. They also identified interactions between the CR1 variant and apoE4 variants associated with AD. Dr. de Jager described additional unpublished work to leverage epigenomic analyses in a similar way.

Work is also under way to define the neuroimmunologic component in these architectures. Dr. de Jager and his collaborators have identified pathways, some of which are related to immune function, that are shared between AD and age-related cognitive decline. They have also conducted systematic analyses of susceptibility using two distinct, highly purified immune cell types and found evidence suggesting a role for the innate immune system in AD. Dr. de Jager and his collaborators are looking further at genes associated with the innate immune system to understand how AD-associated variants in these genes affect the brain and to identify potential targets for intervention.

These projects therefore are using comprehensive information from cohort studies to identify the events linking risk factors with clinical syndromes. This in turn allows them to identify potential strategies to disrupt those causal links.

In response to questions from Council, Dr. de Jager noted that investigators have been enthusiastic about working together. However, they continue to face challenges in storing and managing the data generated from these studies.

Dr. Clifford Rosen of the Maine Medical Center Research Institute spoke about the state of research on Vitamin D supplementation. Such supplementation is widespread, based partly on research showing that vitamin D acts at multiple sites in the human body. However, the evidence supporting vitamin D supplementation is limited—an IOM committee found positive evidence only for skeletal health. Even this evidence is somewhat inconsistent. One 2010 meta-analysis suggested that calcium and vitamin D supplementation reduced the risk for fractures by 60%, but the U.S. Preventive Services Task Force found no effect on hip fracture, and a recent study published in Lancet found no effect on bone mineral density. Data from the Women’s Health Initiative suggest that calcium and vitamin D supplementation reduce the risk for hip fracture by about 12%, but this finding was not statistically significant.

He next provided a closer look at data from randomized, controlled trials. While the Women’s Health Initiative, in which participants received an average of 365 units of vitamin D per day, suggested a reduced risk for fractures, this finding was not statistically significant. A French study that was included in the 2010 IOM meta-analysis found that calcium and vitamin D supplementation reduced risk by 30%, but the data also suggest that only individuals with severe vitamin D deficiencies might benefit from supplementation. This suggestion is consistent with a recent microstructural analysis showing that bones are more fragile in individuals with very low vitamin D levels. Such evidence suggests that only a subset of individuals might benefit from calcium and vitamin D supplementation.

This suggestion is consistent with in vitroand mouse studies. Receptors for vitamin D are expressed globally in the body. Although bones appear to be normal in mice globally deficient for the vitamin D receptor, these knockouts die within 2 to 3 months because of low serum calcium levels. Treatment with exogenous calcium can rescue this phenotype, as does overexpression of the vitamin D receptor only in the intestine. Blood calcium levels are normal in mice deficient in intestinal vitamin D receptors, but only because of hyperparathyroidism and increased vitamin D. These findings suggest that a key function of vitamin D is to promote calcium absorption. However, the addition of vitamin D to osteoblasts in vitro suppresses mineralization by enhancing the level of pyrophosphates and increasing bone resorption.

Data from the Women’s Health Initiative suggest that the number of falls is the largest factor associated with the risk for fractures, with three or more falls increasing risk more than twofold. However, analyses by IOM and others have found no evidence that vitamin D supplementation has an impact on falls. Consistent with these findings, a recent randomized trial in Norway found no risk reduction associated with vitamin D and calcium supplementation. Dr. Rosen suggested that one issue might be the way falls are defined. Indeed, a recent publication found that supplementation reduced risk for multiple falls requiring medical attention.

Dr. Rosen concluded by noting that more basic studies of vitamin D are needed and by outlining potential research questions. The Council discussed potential harms associated with blanket vitamin D supplementation in the general population, the likelihood that this practice will change in light of the inconsistent evidence, and potential subgroups for further study. Council members also noted difficulties in recruiting for placebo-controlled trials in light of widespread use of vitamin D and the general sense that vitamin D supplementation is protective.

Division of Geriatrics and Clinical Gerontology (DGCG): Diabetes Prevention in the Aging Population: The Diabetes Prevention Program Outcome Study—Next Steps

In the United States, approximately 25 million individuals have type 2 diabetes, and an estimated 75 million are pre-diabetic. This epidemic is caused partly by the overall aging of the population; the risk for diabetes is higher among older adults, compared with younger populations. However, obesity plays a large role. Obesity rates have increased substantially over the past 30 years, and the risk for diabetes increases 100-fold at body mass indexes higher than 35.

Dr. David Nathan, of the Diabetes Center and Clinical Research Center at Massachusetts General Hospital, summarized the Diabetes Prevention Program (DPP), a cohort study to prevent or slow the development of type 2 diabetes in persons at high risk. Participants, approximately half of whom were from high-risk groups, were randomized to receive placebo, metformin, or an intensive lifestyle intervention. The intensive lifestyle intervention, which aimed for a weight loss of 7% or more, involved 150 minutes or more of moderate-intensity exercise per week. Twenty percent of the study population was older than 60 years. While results from DPP showed that both metformin and lifestyle intervention resulted in weight loss, the effect was greater for the lifestyle intervention group. This group also showed higher-than-expected levels of physical activity. Cumulative incidence of diabetes was reduced by 31% in the metformin group and by 58% in the lifestyle intervention group. Dr. Nathan pointed out that the lifestyle intervention was particularly effective among older participants, with a 71% reduction in risk, while metformin was more effective in younger and more obese patients.

The DPP Outcomes Study (DPPOS) is evaluating the longer-term effects of the original DPP interventions on further development of diabetes, diabetes-associated complications, and economic implications among 3,000 DPP participants. All participants have received the lifestyle intervention in addition to their initial randomized DPP intervention. During the first and second 5-year periods, diabetes incidence declined for all three groups’ metformin, lifestyle and placebo to that of the initial DPP lifestyle group. Incidence is reduced by 34% for the lifestyle group and by 18% for the metformin group after 10 years in DPPOS compared to placebo, and by 27% for the lifestyle group and 12% for the metformin group after 16 years. Lifestyle intervention also appears to lower cardiovascular risk factors and the number of medications participants take. DPPOS also found that both metformin and lifestyle intervention resulted in more gains in quality of life, compared with placebo. In addition, DPPOS found a cost-savings of $200 to $300 for metformin and $1,000 for the lifestyle intervention.

DPPOS involves several collaborations and includes several ancillary studies, and it has generated more than 100 publications. Dr. Nathan concluded his presentation by suggesting that continuation of DPPOS will provide valuable information about the continuum from prediabetes to advanced diabetes with complications, with several public health implications. Additional research questions include the effects of long-term metformin on cancer and cardiovascular events, the long-term clinical course among individuals with “prediabetes,” and the effects of diabetes delay or prevention on longer-term microvascular and cardiovascular outcomes.

Discussion focused on the importance of adherence, both for the metformin and lifestyle interventions, as well as cognitive measures in DPPOS.

Division of Behavioral and Social Research (DBSR): The Cost and Benefits of Expanding Medicaid: Evidence from the Oregon Health Insurance Experiment

Dr. Katherine Baicker of the Harvard School of Public Health described a surprising opportunity to conduct a randomized trial of Medicaid in the State of Oregon.Medicaid has been in place for 50 years, but what it does exactly, and whether it provides a benefit, has been under debate. These questions have been difficult to answer because the Medicaid population is poorer, more disabled, or more likely to have high-cost diseases, compared with the general population. In addition, Medicaid programs differ by state, and no factors explain clearly why some states are more generous than others. Recent observational studies suggest that mortality is higher among individuals on Medicaid, but these studies are confounded by selection issues. The RAND health insurance experiment, the only randomized controlled trial studying the effects of health insurance, involves a much different population: individuals who are insured, especially for high-cost health events.

In 2008, faced with a waiting list for Medicaid services but a limited number of spaces in the program, the State of Oregon held a lottery to determine which individuals could apply for Medicaid. The lottery served as the main source of variation for the Oregon Health Insurance Experiment, a collaborative effort to assess a broad range of outcomes. The study collected demographic information and data from administrative records, mail and in-person surveys, and other measurements.

Dr. Baicker, showed results from the first 2 years of the Oregon Health Insurance Experiment. The study found that Medicaid expansion resulted in substantial increases in health care utilization, as shown by increases in hospitalization, primary care visits, and emergency department visits. Expansion also was associated with a reduction in the financial strain associated with health care consumption: for example, individuals were 25% less likely to have bills that were sent to collections. Survey data suggested large improvements in self-reported physical and mental health. Although clinical assessments showed a dramatic decline in depression, they showed no detectable effects on control of blood sugar, blood pressure, or cholesterol. Among patients with diabetes, there was an increase in diagnosis and medications.

Dr. Baicker emphasized caution about interpretation and noted limitations for generalizability. For example, she pointed out that the number of lives covered by this approach is small in terms of the overall health care system, that longer-term results might differ from the results she presented, and that the Oregon population might not represent the rest of the United States. However, she pointed out that the data thus far can eliminate the two extreme views of Medicaid. Beneficiaries appear to be better off on the program, refuting the pessimistic view that providers are not paid enough and that beneficiaries are actually killed on the program. At the same time, the increased health care utilization, even in emergency departments, refutes the overly optimistic view that Medicaid expansion will prevent overuse of the emergency departments and that chronic diseases will be managed well enough to save costs.

Council discussion centered around questions on adherence, the need for more randomized studies in health economics, the possibility that pent-up need might have affected the initial results, and the possibility of cost-shifting for emergency department care.

Laboratory of Epidemiology and Population Sciences (LEPS)

LEPS prospectively studies the natural history, distribution, and consequences of disease; develops methods to study aging in the population; and studies interactions between genetics and the environment. The Laboratory operates under the premise that aging is not one single disease and that everyone older than 65 years is not the same, but that exposures early in life affect the trajectory of aging. LEPS has engaged in several collaborations, both within the United States and across the globe, and it has developed several resources, including cohort- and community-based studies such as the Health, Aging, and Body Composition (Health ABC) study and the Action to Control Cardiovascular Risk in Diabetes brain substudy (ACCORD-MIND).

The Neuroepidemiology Section has added a magnetic resonance imaging component to the Coronary Artery Risk Development in Young Adults (CARDIA) study, which is funded by the National Heart, Lung, and Blood Institute, to study 25-year trajectories between risk factors and brain outcomes.

The Interdisciplinary Studies of Aging Section has developed several cohorts, including Health ABC and the Age-Gene/Environment Susceptibility study in Reyjkavik (AGES-Reyjkavik) to answer questions about bone quality, sarcopenia, obesity, and low-level movement.

The Behavioral Epidemiology Section has identified sex differences in the association between serum ferritin levels and risk for coronary heart disease. The Section also is using data from the Healthy Aging in Neighborhoods of Diversity Across the Lifespan (HANDLS) study to explore racial differences in sleep duration and inflammation, and it is using data from both HANDLS and the Health and Retirement Study to explore how sex discrimination amplifies the effect of antagonism on increased risk of cigarette smoking.

The Health Disparities Section has taken advantage of HANDLS data and a core laboratory to explore racial variations in vitamin D and vitamin D-binding protein levels. Some of these findings were published in the New England Journal of Medicine in 2013.

Dr. Launer concluded her presentation by noting that LEPS will continue to lead in exploiting advances in technology and the integration among epidemiology, basic, and clinical investigations to explore the epidemiology of aging.

Laboratory of Molecular Gerontology (LMG)

Dr. Vilhelm Bohr, LMG Chief, highlighted the Laboratory’s work exploring the contributions of DNA damage and genomic instability to aging and age-associated decline and disease. One area of focus is the RecQ family of helicases, which serve as guardians of the genome and have been implicated in cellular senescence and disorders of premature aging, such as the segmental progerias. LMG has found that proteins associated with Fanconi anemia cooperate with other helicases, particularly at the replication formed under conditions of replication stress.

LMG has also been interested in the mitochondrial theory of aging, which posits that accumulation of damage and mutations in the mitochondrial DNA leads to mitochondrial and cellular dysfunction and, ultimately, to aging. The Laboratory has explored mitochondrial DNA repair processes in mouse models and humans, and it has developed a database of disease-associated mitochondrial dysfunction, for example in diseases such as Cockayne syndrome, ataxia, and XPA deficiency. LMG findings suggest a vicious cycle comprising defects in nuclear DNA repair, mitochondrial DNA dysfunction, and additional damage to the nuclear DNA. Other work is exploring the effects of oxidative DNA damage on telomere length homeostasis. Dr. Bohr also described work in mouse models to explore links between DNA repair capacity and risk for AD.

Laboratory of Behavioral Neuroscience (LBN)

Dr. Susan Resnick, LBN Chief, focused her presentation on the Laboratory’s work investigating predictors of cognitive impairment and resilience. This research program, which the Laboratory began 20 years ago, has contributed to the temporal changes described by the revised Jack model of biomarker progression in dementia. Although this model is still hypothetical, empirical data suggests a 15- to 20-year lag between amyloid deposition and other biomarkers and the clinical syndrome of AD-related dementia. Imaging and other biomarkers have aided not only in the diagnosis of cognitive decline and AD, but also in characterizing preclinical criteria for AD.

Dr. Resnick described work with the Baltimore Longitudinal Study of Aging (BLSA). Imaging done as part of a BLSA substudy has shown widespread tissue loss throughout the brain over time. This tissue loss is accelerated in a subgroup of participants who are normal but later develop cognitive impairment. Imaging also has shown differences in cerebral blood flow between participants who develop cognitive impairment and those who do not. These changes suggest a shift in the balance of activity in the brain and support the hypothesis that the initial period of impairment involves compensatory changes or even hyperexcitability. Dr. Resnick also described unpublished work to identify factors that modify the risk for AD and Ab deposition. She noted, however, that this is a complex picture, as suggested by recently published findings that apoE genotype affects risk only in individuals who do not carry the risk allele for the CR1 gene. LBN has also been using the BLSA database to examine resilience. For example, recent work suggests that asymptomatic AD is associated with lower neuroticism and higher consciousness.

Dr. Resnick concluded her presentation by discussing the Laboratory’s intent to use the information it has gathered to investigate other mid- and late-life factors affecting AD risk. Dr. Resnick and Dr. Launer have discussed pulling together data from a variety of samples. LBN aims to move beyond group differences and develop a multimodal, multiregional approach to identify individuals at risk for AD. LBN also has started to integrate cognitive and motor data to examine BLSA data with respect to brain changes, health, and disability.

ADJOURNMENT

The open session of the 121st meeting of the NACA adjourned at 1 p.m. on September 18, 2013. The next meeting is scheduled for February 25–26, 2014.

REVIEW OF INTRAMURAL RESEARCH PROGRAM

This portion of the meeting was closed to the public, in accordance with the determination that it concerned matters exempt from mandatory disclosure under Sections 552(b)(c)(4) and 552(b)(c)(6), Title 5, U.S. Code and Section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix).3

I hereby certify that, to the best of my knowledge, the foregoing minutes and attachments are accurate and complete.4

Richard J. Hodes, M.D.
Chairman, National Advisory Council on Aging
Director, National Institute on Aging

Prepared by Robin Barr, D.Phil.
With assistance by Rose Li and Associates, Inc.

For the record, it is noted that members absented themselves from the meeting when the Council discussed applications (a) from their respective institutions or (b) in which a conflict of interest may have occurred. This procedure only applied to applications that were discussed individually, not to “en bloc” actions. (Back to text.)

Dr. Anderson was present on Tuesday, February 25, 2014, but not at the open session on Wednesday, February 26, 2014. (Back to text.)

For the record, it is noted that members absented themselves from the meeting when the Council discussed applications (a) from their respective institutions or (b) in which a conflict of interest may have occurred. This procedure applied only to applications that were discussed individually, not to “en bloc” actions. (Back to text.)

These minutes will be approved formally by Council at the next meeting on September 18–19, 2013, and corrections or notations will be stated in the minutes of that meeting. (Back to text.)